Isobutylbenzene synthesis

There have been many commercial and laboratory publications on the synthesis of ibuprofen. Two of the most popular ways to obtain ibuprofen are the Boots process and the Hoechst process. The Boots process is an older commercial process developed by the Boots Pure Dmg Company, the discoverers of ibuprofen in the 1960s, and the Hoechst process is a newer process developed by the Hoechst Company. Most of these routes to Ibuprofen begin with isobutylbenzene and use Friedel-Crafts acylation. The Boots process requires six steps, while the Hoechst process, with the assistance of catalysts, is completed in only three steps (Figure 20.2). 

These ketones are important intermediates in the synthesis of fragrances of the musk type, of UV absorbents and of pharmaceuticals such as paracetamol, ibuprofen, S-naproxen. Thus, in the processes of ibuprofen synthesis (9), the first classical step is the acetylation of isobutylbenzene with acetic anhydride in presence of HF (Hoechst process) or of A1C13 (Boots process) ... 

Acylation of isobutylbenzene with acetic anhydride leads with high yield and selectivity to para-acetylisobutylbenzene (Eq. 9) which is an intermediate in the synthesis of ibuprofen, an important antiinflammatory drug [18]. With H/1 zeolite at 140 °C after 1 h the yield is 80 % with 96 % para selectivity. Acylation of tetra-lin with acid chlorides and different zeolites has also been studied [19], For this reaction again acetyl chloride is much less reactive than higher acid chlorides such as butanoyl or octanoyl chloride. The selectivity is in favor of the 2-substituted isomer (85-90%) and limited quantities of the 1 isomer (10-15%) are formed (Eq. 10). 

In the presence of Re207/Al203 that has been pretreated with Cu(N03)2 to suppress side reactions, the cross-metathesis of 2,4,4-trimethyl-2-pentene with 4-vi-nylcyclohexene (Eq. 10) proceeds with >15% selectivity [29]. The product iso-butenyl cyclohexene can be converted to isobutylbenzene, which is the starting material for the synthesis of the over-the-counter analgesic, ibuprofen. 

For example, isobutylbenzene as starting material for ibuprofen synthesis is produced by side-chain alkylation of toluene with solid super-base by Sumitomo (Eq. 8-28). 

Similarly, acylation of isobutylbenzene with acetic anhydride over H-Beta catalyst at 140°C can afford p-acetylisobutylbenzene (Figure 11.10), which is an intermediate in the synthesis of antiinflammatory drug ibuprofen, in 80% yield and 96% para-selectivity [41]. 

A special value of Friedel-Crafts acylations in synthesis is for the preparation of unrearranged alkylbenzenes, as illustrated by the preparation of isobutylbenzene. 

Give an efficient synthesis of (2-methylpropyl)benzene (isobutylbenzene, the starting material for the preparation of ibuprofen see Exercise 16-10), starting from benzene. [Hint What would you expect as the major monosubstitution product of Friedel-Crafts alkylation of benzene with l-chloro-2-methylpropane (isobutyl chloride) ]... 

Outline a synthesis of 2-methyH-phenylpropane (isobutylbenzene) starting from benzene using a Friedel-Crafts reaction. 

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